Controlled release pharmaceutical formulations

ABSTRACT

Disclosed herein are drug release polymer compounds and compositions comprising prostacyclin compounds of Formula (I), and methods of preparing the same. A preferred polymer has a repeating unit of the following structure:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application No.61/817,462, filed Apr. 30, 2013, the entire contents of which areincorporated herein by reference.

FIELD

The present invention relates to controlled release formulations ofself-polymerizing drug moieties comprising one or more carboxylic acidgroups and one or more hydroxyl groups.

BACKGROUND

Polymeric systems for the delivery of bioactive materials such as drugsare well known in the art, but many inherent problems persist and thereis a need for a controlled-release pharmaceutical formulation with highloading, precisely controlled drug release and low toxicity.

Variations in blood concentration of a drug can lead to inadequateefficacy if too little drug is present in the blood or at the site ofaction for any length of time, and to side effects when there is toomuch drug in the bloodstream or at the site of action. An ideal drugadministration modality would achieve a steady concentration of the drugin the ‘therapeutic window’ sufficient to achieve maximal efficacy whilenot high enough to engender side effects. In practice, this idealconcentration of drug often transpires to be a compromise betweenefficacy and side effects. For many drugs (e.g., prostacyclin drugs),the breadth of this therapeutic window is rather narrow. The achievementof a ‘flat’ concentration profile for treprostinil, for example, isapproximated by continuous subcutaneous infusion using a pump andachieves a favorably low peak-to-trough variation of 20-30% (Wade, M.,et al., Journal of Clinical Pharmacology, 2004, 44(5): 503-509).However, administration via subcutaneous infusion gives rise tosignificant injection site pain and inflammation, and administration viaindwelling catheter poses a risk of infection. So far, attempts toachieve the objective of having an alternative mode of administration tocontinuous infusion have not been highly successful. There is,therefore, a need to provide a controlled release formulation whichavoids the risk of infection or pain at the infusion site, whileachieving a flat concentration profile of drug in the therapeuticwindow.

U.S. Pat. No. 7,417,070 discloses certain esters, salts, and sustainedrelease oral compositions comprising treprostinil.

U.S. Pat. No. 6,242,482 discloses certain long-acting prostaglandincompositions, some of which include treprostinil.

SUMMARY

In one aspect, a drug release polymer is provided, wherein the polymerincludes an active pharmaceutical moiety which comprises at least onecarboxylic acid group and at least one hydroxyl group. In someembodiments, the active pharmaceutical moieties form monomeric unitscovalently bonded to each other to form a polymer backbone, and theactive pharmaceutical moieties are capable of being released at a ratethat is dependent on the extent of biodegradation of the polymerbackbone. In some embodiments, the active pharmaceutical or drug moietyis a prostacyclin compound. In some embodiments, the prostacyclincompound is selected from epoprostenol, treprostinil, beraprost,iloprost, cicaprost, or a prostaglandin 12. In one embodiment, theprostacyclin compound is treprostinil. In a further embodiment, theprostacyclin compound has the following structure (I)

-   -   wherein        -   represents a single or a double bond;        -   Z¹ and Z² each independently represents an O or CH₂;        -   p=0 or 1;        -   m=1, 2, or 3;        -   R¹ represents a H or an acid protective group;        -   R² and R³ each independently represents a H or a hydroxyl            protective group;        -   R⁴ represents H and the other represents a C₁₋₆ alkyl; and        -   R⁵ represents a C₁₋₆ alkyl group or C₂₋₈ alkynylene group.

The prostacyclin compound forms various configurations of drug releasepolymers via formation of ester bonds between the carboxylic acid groupon one prostacyclin molecule and the hydroxyl group on the otherprostacyclin molecule. In some embodiments, in addition to theprostacyclin compound, the polymer also includes a co-monomer covalentlybonded to the carboxylic acid group of one drug moiety and the hydroxylgroup of a second drug moiety. In some embodiments, the co-monomer is6-hydroxyhexanoic acid or hydroxyl-polyethylene glycol-carboxylic acid.

In one embodiment, the recurring unit in the polymer has a structureselected from the group consisting of Formula (IIa), (IIb) and (IIc):

In another aspect, a pharmaceutical composition comprising the drugrelease polymer and a pharmaceutically acceptable excipient is provided.In some embodiments, upon administration of the pharmaceuticalcomposition to a patient, the drug release polymer degrades initiallyinto inert polymer fragments, which thereafter give rise to active drugonly after a time interval. In some embodiments, the pharmaceuticalcomposition exhibits accelerating release of the drug moiety. In someembodiments, the pharmaceutical composition is used as a medicament forinjection, preferably subcutaneous or intramuscular injection. In otherembodiments, the pharmaceutical composition is used as a medicament forimplant.

In still another aspect, a method is provided for producing a drugrelease polymer, comprising esterifying a drug moiety which comprises atleast one carboxylic acid group and at least one hydroxyl groupprostacyclin compound in the presence of a coupling agent and acatalyst. In some embodiments, the coupling agent isN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide orN,N′-Dicyclohexylcarbodiimide. In other embodiments, the catalyst is4-(Dimethylamino)pyridine. In some embodiments, the method furthercomprises blocking one or more carboxylic acid groups in excess of onecarboxylic group, prior to esterification. In other embodiments, themethod further comprises blocking one or more hydroxyl groups, in excessof one hydroxyl group, prior to esterification. In some embodiments, theone or more hydroxyl groups are blocked using trimethylsilyl chloride ort-butyldimethylsilyl chloride.

In another aspect, a method is provided for treating, controlling,delaying or preventing in a mammalian patient in need of the treatmentof one or more conditions comprising administering to said patient adiagnostically and/or therapeutically effective amount of the drugrelease polymer or a pharmaceutical composition containing the drugrelease polymer. In a preferred embodiment, the drug moiety istreprostinil, and the method is a method for treating pulmonaryhypertension in a patient in need thereof.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows one embodiment of the structure of a drug moiety forming arepeating unit in the polymer.

FIG. 2 shows one embodiment of the polymer of the invention, whereinboth the ring hydroxyl and the chain hydroxyl of treprostinil areinvolved in backbone bonds of the polymer leading to a branchedstructure.

FIG. 3 shows one embodiment of a linear polymer formed by utilizing a‘ring-hydroxyl-blocked’ form of treprostinil and involving only thechain hydroxyl and not the ring hydroxyl.

FIG. 4 shows another embodiment of a linear polymer formed by utilizinga ‘chain-hydroxyl-blocked’ form of treprostinil and involving only thering hydroxyl and not the chain hydroxyl.

FIG. 5 shows one embodiment of a heteropolymer of treprostinil formed inthe presence of 6-hydroxyhexanoic acid as a co-monomer.

FIG. 6 shows one embodiment of a heteropolymer of treprostinil formed inthe presence of a hydroxyl-PEG-carboxylic acid co-monomer.

FIG. 7 shows the hydrolytic behavior of a soluble polymer of the presentinvention having 11 monomeric units (circles) and 10 inter-monomer bonds(A), at time zero (A) and at linear time intervals (B-H).

DETAILED DESCRIPTION

Various embodiments are described hereinafter. It should be noted thatthe specific embodiments are not intended as an exhaustive descriptionor as a limitation to the broader aspects discussed herein. One aspectdescribed in conjunction with a particular embodiment is not necessarilylimited to that embodiment and can be practiced with any otherembodiment(s).

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the elements (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the embodiments and does not pose alimitation on the scope of the claims unless otherwise stated. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential.

The expression “comprising” means “including, but not limited to.” Thus,other non-mentioned substances, additives, carriers, or steps may bepresent. Unless otherwise specified, “a” or “an” means one or more.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations. Each numerical parameter should atleast be construed in light of the number of reported significant digitsand by applying ordinary rounding techniques. The term “about” when usedbefore a numerical designation, e.g., temperature, time, amount, andconcentration, including range, indicates approximations which may varyby (+) or (−) 10%, 5% or 1%.

As used herein, C_(m-n), such as C₁₋₁₂, C₁₋₈, or C₁₋₆ when used before agroup refers to that group containing m to n carbon atoms.

The term “alkoxy” refers to —O-alkyl.

As used herein, “halo” or “halogen” or even “halide” can refer tofluoro, chloro, bromo, and iodo.

The term “alkyl” refers to monovalent saturated aliphatic hydrocarbylgroups having from 1 to 12 carbon atoms (i.e., C₁-C₁₂ alkyl) or 1 to 8carbon atoms (i.e., C₁-C₈ alkyl), or 1 to 4 carbon atoms. This termincludes, by way of example, linear and branched hydrocarbyl groups suchas methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—), isopropyl((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—), sec-butyl((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl (CH₃CH₂CH₂CH₂CH₂—), andneopentyl ((CH₃)₃CCH₂—).

The term “aryl” refers to a monovalent, aromatic mono- or bicyclic ringhaving 6-10 ring carbon atoms. Examples of aryl include phenyl andnaphthyl. The condensed ring may or may not be aromatic provided thatthe point of attachment is at an aromatic carbon atom.

Combinations of substituents and variables are only those that result inthe formation of stable compounds. The term “stable,” as used herein,refers to compounds which possess stability sufficient to allowmanufacture and which maintains the integrity of the compound for asufficient period of time to be useful for the purposes detailed herein.

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide an active compound. Examples ofprodrugs include, but are not limited to, derivatives of a compound thatinclude biohydrolyzable groups such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues (e.g., monophosphate, diphosphate or triphosphate).

As used herein, “hydrate” is a form of a compound wherein watermolecules are combined in a certain ratio as an integral part of thestructure complex of the compound.

As used herein, “solvate” is a form of a compound where solventmolecules are combined in a certain ratio as an integral part of thestructure complex of the compound.

“Pharmaceutically acceptable” means in the present description beinguseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable andincludes being useful for veterinary use as well as human pharmaceuticaluse.

“Pharmaceutically acceptable salts” mean salts which arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity. Such salts include acid addition saltsformed with organic and inorganic acids, such as hydrogen chloride,hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid,acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid,methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid,tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.Base addition salts may be formed with organic and inorganic bases, suchas sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine,N-methylglucamine, choline and the like. Included are pharmaceuticallyacceptable salts or compounds of any of the Formulae herein.

Depending on its structure, the phrase “pharmaceutically acceptablesalt,” as used herein, refers to a pharmaceutically acceptable organicor inorganic acid or base salt of a compound. Representativepharmaceutically acceptable salts include, e.g., alkali metal salts,alkali earth salts, ammonium salts, water-soluble and water-insolublesalts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.

As used herein, “protecting group” or “protective group” is used asknown in the art and as demonstrated in Greene, Protective Groups inOrganic Synthesis.

As used herein, “hydroxyl protective group” or “hydroxyl protectinggroup” or “hydroxyl blocking group” refers to the generally understooddefinition of an alcohol or hydroxyl protecting group as defined in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons,1991 (hereinafter “Greene, Protective Groups in Organic Synthesis”).

As used herein, “acid protective group” or “acid protecting group” or“carboxylic acid blocking group” refers to the generally understooddefinition of protection for the carboxylic acid group as defined in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons,1991 (hereinafter “Greene, Protective Groups in Organic Synthesis”).

In various aspects, drug polymers are provided for sustained release ofan injected or implanted drug in order to achieve favorablepharmacokinetics with minimal peak-to-trough variation of drugconcentration in the blood. The drug polymers are designed to achieve abetter approximation of the ideal continuous, steady, bloodconcentration profile which is approached most closely by continuousdrug infusion, and which is difficult to achieve with current sustainedrelease methodologies.

The present technology is adaptable to any drug containing one or morecarboxylate groups and additionally one or more hydroxyl groups (i.e.,primary or secondary alcohols). In the drug release polymer, the drugitself acts as a monomer. Therefore, in one embodiment, the onlyingredient in the polymer is the drug molecule, minus abstracted watermolecules generated in the formation of ester bonds during polymerformation. The ester bonds, being metastable, will hydrolyse in thepresence of water in body fluids following administration, causingbreakdown of the polymer, resulting in the re-generation of monomericdrug molecule from the inactive polymer prodrug, in a staged manner, viaoligomeric, inactive, intermediates.

Prostacyclin compounds are an example of a drug containing one or morecarboxylate groups and one or more hydroxyl moieties. These include bothstable prostacyclin compounds such as treprostinil and beraprost (andthe 314d active isomer of beraprost) and less-stable prostacyclincompounds such as prostacyclin (prostaglandin-I₂) itself.

In the case of prostacyclin compounds, existing drug-polymerreversible-covalent conjugates (such as PEG-drug conjugates of the typedescribed by Pasut, G. and F. M. Veronese, Advanced drug deliveryreviews, 61(13): 1177-1188, 2009) for bolus injection, and those thatare described in patents and applications by Ascendis Pharma (WO2013/024051, WO 2013/024052, WO 2013/024053), prolong the absorptionphase and also the elimination phase of the drug from the bloodstream,resulting in improved longevity in the blood of a drug molecule.However, in these systems (designed to create a circulating reservoir ofthe drug in the bloodstream), the drug concentration in the bloodinevitably undergoes an exponential decline shortly after the attainmentof a maximal blood concentration (Cmax). This exponential decay preventsthe drug ever achieving a true ‘zero-order’ release kinetic, whereinthere is a constant blood concentration. During the decay phase,hydrolysis of the drug-polymer bond takes place at a fixed rate, leadingthe polymer-delivered drug to follow a somewhat faster eliminationkinetic than the polymer conjugate (although much slower than that ofthe free drug), based on its shorter half-life as a free compound.Rather than follow a ‘sawtooth’ blood concentration profile, which isthe case for free compound in non-sustained release formulations,whether inhaled, ingested or injected (bolus), the classicalcovalent-release drug conjugate has a smoother, more undulatingconcentration profile in the blood. Nevertheless, the significantpeak-to-trough variation in blood concentration that remains may not bemarkedly better than other alternative modes of sustained delivery ofthe free compound (such as sustained release oral tablet formulations),resulting in periods of inadequate efficacy or undesirable toxicity ofthe drug, when blood concentrations are in ‘trough’ or ‘peak’ zones(respectively). The new drug polymers of the present technology providesolutions to the problem of residual peak-to-trough variation inherentin existing drug-polymer conjugate systems.

In one aspect, a drug release polymer is provided, wherein the polymerincludes a drug moiety which comprises at least one carboxylic acidgroup and at least one hydroxyl group. In some embodiments, the drugmoiety is a prostacyclin compound. In some embodiments, the drug releasepolymer is a controlled release polymer. In some embodiments, the drugmoieties form monomeric units that are covalently bonded to each otherto form the polymer backbone, and wherein the drug moieties are capableof being released in a manner dependent upon the extent of breakdown ofthe polymer backbone. Thus, the drug moiety is an integral part of thepolymeric chain and is embedded and comprises the fabric of the polymer.This feature distinguishes the polymers of the present invention fromprior drug polymer covalent sustained release systems, wherein thepolymer is made from a different substance (e.g. PEG made from ethyleneglycol) than that of the drug.

In some embodiments, the drug release polymer includes linear andbranched homopolymers and heteropolymers of a prostacyclin compound. Anyprostacyclin which has one or more carboxylic acid group and one or morehydroxyl group can be utilized for the drug release polymer. Examples ofsuch prostacyclin compounds include, but are not limited to,epoprostenol, treprostinil, beraprost, iloprost, cicaprost,prostaglandin 12. In one embodiment, the prostacyclin compound istreprostinil. In another embodiment, the prostacyclin compound isberaprost.

In one embodiment, the prostacyclin compound has the following structure(I)

-   -   wherein        -   represents a single or a double bond;        -   Z¹ and Z² each independently represents an O or CH₂;        -   p=0 or 1;        -   m=1, 2, or 3;        -   R¹ represents a H or an acid protective group;        -   R² and R³ each independently represents a H or a hydroxyl            protective group;        -   R⁴ represents H and the other represents a C₁₋₆ alkyl; and        -   R⁵ represents a C₁₋₆ alkyl group or C₂₋₈ alkynylene group.

In some embodiments, Z¹ is a O and Z² is CH₂. In some embodiments, Z¹ isCH₂ and Z² is O.

In some embodiments, R¹ is H. In other embodiments, R¹ is an acidprotective group. Suitable carboxylic acid protective groups R¹ areknown in the art and include the ester derivatives of a carboxylic acidgroup commonly employed to block or protect the carboxylic acid groupwhile reactions are carried out on other functional groups on thecompound. Exemplary groups for the protection of the carboxylate groupinclude allyl, methyl, ethyl, nitrobenzyl, dinitrobenzyl,tetrahydropyranyl, methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl,trimethylbenzyl, pentamethylbenzyl, methylenedioxybenzyl, benzhydryl,4,4′ dimethoxybenzhydryl, 2,2′4,4′-tetramethoxybenzhydryl, t-butyl,t-amyl, trityl, 4 methoxytrityl, 4,4′-dimethoxytrityl,4,4′,4″-trimethoxytrityl, 2-phenyl-prop-2-yl, trimethylsilyl,t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,b-(tri-methylsilyl)ethyl, b (di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. In someembodiments, R¹ is a benzyl, tertiary-butyl, dimethoxy benzyl,nitrobenzyl or a dinitrobenzyl group.

In some embodiments, R² and R³ each independently is a H. In otherembodiments, R² and R³ each independently is a hydroxyl protectivegroup. Suitable groups for the protection of the hydroxyl groups areknown in the art and include, but are not limited to, methyl, t-butyl,tetrahydropyranyl, benzyl, methoxybenzyl, nitrobenzyl, tertiary butyldimethyl silyl (TBDMS), trimethylsilyl (TMS), tertiary methyl dimethylsilyl group, methoxymethyl, methoxyethoxymethyl, allyl, trityl,ethoxyethyl, 1-methyl-1-methoxyethyl, tetrahydropyranyl, ortetrahydrothiopyranyl group. In one embodiment, the hydroxy protectivegroup is tetrahydropyranyl (THP). In some embodiments, R² and R³ eachindependently is a tetrahydropyranyl, benzyl, methoxybenzyl,nitrobenzyl, tertiary butyl dimethyl silyl or a tertiary methyl dimethylsilyl group.

In some embodiments, m is 1 and p is 1. In other embodiments, m is 3 andp is 0.

The prostacyclin compound forms various configurations of drug releasepolymers via formation of ester bonds between the carboxylic acid groupon one prostacyclin compound and the hydroxyl group on the otherprostacyclin compound. For example, with treprostinil, the drug can bedesigned to be a homopolymer in three basic forms, or a number ofheteropolymer variants made with different co-monomers. Treprostinil isthe active ingredient in Remodulin®, and is described in Moriarty, et alin J. Org. Chem. 2004, 69, 1890-1902, U.S. Pat. Nos. 6,441,245,6,528,688, 6,700,025, and 6,809,223, which are incorporated by referencein their entirety. Treprostinil has the following structure (II):

Treprostinil has one carboxylic acid group and two hydroxyl groups—onering hydroxyl group and one chain hydroxyl group. Various homopolymersand heteropolymers can result from the reaction between the carboxylicgroup with either the ring hydroxyl or the chain hydroxyl group ofvarious treprostinil moiety to form esters. Blocking agents can be usedto selectively block either the ring hydroxyl or the chain hydroxylgroup resulting in the formation of various linear or branchedhomopolymers. FIG. 1 shows a structure of a preferred drug moietyforming a repeating unit in the polymer, wherein the letter variables ofthe formula have the same meaning set forth in paragraph 6. Exemplaryhomopolymers and heteropolymers of treprostinil are depicted in FIGS.2-6, wherein all inter-monomer bonds are ester bonds.

The drug release polymers of the present technology function asprodrugs, whereby they release the pharmacologically active form of thedrug moiety by cleavage of the temporary ester group linkages formedbetween the drug moieties.

The drug release polymers of the present technology have a polarity,just like important biopolymers such as DNA, RNA and protein. Whereasnucleic acids have a 5′ and a 3′ end, and proteins have an N-terminusand a C-terminus, which dictate their direction of growth duringbiosynthesis, so the present polymers have a ‘carboxylate end’ and a‘hydroxyl end.’ Polymer chain length can be controlled by variousmethods known in the art, e.g., by incorporating various amounts ofchain terminating reagents. In some embodiments, a drug moiety withcarboxylate protection (methyl, nitrile) can be used to form the end ofa polymer. Increasing amounts of such chain terminating agentsincorporated into a polymerization mixture would give rise to shorterpolymer lengths on average. In other embodiments, a drug moiety with twoblocked hydroxyls and a free carboxylate can be used to limit the lengthof the polymer. In yet other embodiments, incorporation of methanol orethanol (or other primary, secondary or tertiary alcohols) into thereaction mixture after an interval can be used to stop thepolymerization reaction. The time at which the reaction is stopped canbe altered to create polymers of different lengths. In general, longerreaction times will result in longer polymers. It may or may not beappropriate or necessary to remove the chain terminating groups. Forexample, a methyl ester blocking group on a carboxylate could be lefton, whereas a tertiarybutyldimethylsilane, which can be toxic ifliberated, can be removed before administration to humans. Various typesof chain terminating compounds can be used, including those that stopchain elongation at the ‘carboxylate end,’ and those that stop chainelongation at the ‘hydroxyl end,’ or a mixture of the two can be used ifneeded. Chain length can also be controlled by controlling theesterification reaction time.

The drug release polymer can have any suitable length depending on thedesired physiochemical property or the mode of administration. Polymerproperties are described below with parameters defined by theInternational Union of Pure and Applied Chemistry (IUPAC) wherein therange of molecular weights in a non-uniform mixture of chemicallysimilar polymer molecules (i.e. ‘dispersity’) is represented by thesymbol ‘

’ which can refer to either molecular mass or degree of polymerization.It can be calculated using the equation

_(M)=M_(w)/M_(n), where M_(w) is the weight-average molar mass and M_(n)is the number-average molar mass. Exemplary polymer lengths can includechain lengths from about n=2 (i.e. dimer, where all molecules have twomonomeric moieties and there is no dispersity) up to Mn=5000 whereinthere is a distribution of polymer lengths or ‘dispersity’. For forms ofthe polymer having finite dispersity,

_(M) may conveniently be in the range 1.1-1.3. Where it is particularlyimportant to have a rather uniform distribution of polymer lengths, e.g.for an accelerating release soluble polymer designed to form acirculating depot in the bloodstream, this may be controlled duringpolymerization by the timed addition of suitable terminating agents,such as those described herein, to achieve values of

_(M) in the range 1.01-1.1

In still another aspect, a method for producing a drug release polymeris provided. In some embodiments, the method comprises esterifying amonomeric drug moiety which has one or more carboxylic acid groups andone or more hydroxyl groups. In some embodiments, the method comprisesesterifying a prostacyclin compound.

Suitable drug candidates for polymer formation by ester bond formation,include drugs which have at least one alcohol (hydroxyl) group, and atleast one carboxylate group. In some embodiments, the drug has two ormore hydroxyl groups. In some embodiments, if the drug has more than onehydroxyl group, most favorably it does not have more than onecarboxylate because this may result in the formation of non-extendibledimers rather than the desired polymeric product. In some embodiments,the drug has more than one carboxylate groups and one hydroxyl group. Insuch cases, protection of the additional carboxylate groups is requiredin order to allow for productive polymer formation.

The various polymer types described herein can have differing degrees ofpolymerization, from dimer to trimer and beyond, to potentially containhundreds of monomeric moieties per polymer. All of these polymers,including small oligomers, such as dimer and trimer, can be useful fordrug delivery purposes. In their simplest form, where the only monomericingredient is drug molecule, these polymers or prodrugs have the uniquequality of having no additional chemical moieties over and above theoriginal drug substance. Therefore, their toxicological properties wouldnot vary significantly from the original drug substance. In the case ofprostacyclin compounds, such as those described herein, theirdose-limiting toxicity would be the pharmacological toxicity of theprostacyclin class of compounds. Such adverse effects, if any, can bemanaged more effectively by sustained or accelerating release of thedrug from the polymer.

Suitable esterification process conditions are known in the art. In oneembodiment, the esterification process is conducted using the Steglichesterification reaction. In some embodiments, the method comprisesesterifying a prostacyclin compound in the presence of a coupling agentand a catalyst. In some embodiments, the coupling agent isN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide orN,N′-Dicyclohexylcarbodiimide. In some embodiments, the catalyst is4-(Dimethylamino)pyridine. In some embodiments, the polymerizationreaction is conducted using a Steglich esterification process asdescribed by Höfle, G., W. Steglich, et al. Angewandte ChemieInternational Edition in English, 1978, 17(8), 569-583. Such reactionshave been reported to attach protected drugs to linker moieties (WO2013/3024051, WO 2013/3024052, WO 2013/3024053) in order to achieve adefined metastable ester linkage between a linker and the drug moietyand to allow subsequent conjugation of this assembly to a polymer.Conversely, the aim of the present technology is to create a drugpolymer, wherein the monomers are primarily drug molecules, and comprisepart of the backbone of the polymer and do not comprise (orpredominantly do not comprise) appendages on the end of a polymer chain.Fewer reactions are required to achieve the drug-polymers of the presentinvention. An alternative method of polymer formation is to conduct thepolymerizing esterification reaction using acidic alumina andmethanesulfonic acid (Al₂O₃/MeSO₃H (AMA)) as described in detail bySharghi et al. (H. Sharghi, Babak Kaboudin, J. Chem. Research (S), 1998,pp. 628-629). This method is particularly suited to creating monoestersfrom a carboxylate compound and a diol, such as ethylene glycol. howeverit should be recognized in the present invention that prostacyclin drugssuch as treprostinil and beraprost, having both carboxylate and diolfunctionalities in the same molecule, in the absence of other extraneousdiol compound, and unlike the compounds studied by Sharghi, willpolymerize. Unlike Steglich esterification, which can be conducted atroom temperature, the Sharghi method requires heating at about 80° C.According to this method Al₂SO₃ (a solid) and MeSO₃H (a liquid) are usedin molar ratio of 1:5 at 80° C. for between 7 and 120 mins, or until anacceptable yield of product is obtained.

In some embodiments, wherein the drug moiety includes more than onecarboxylic acid or hydroxyl group, the method further comprises blockingone or more of the additional carboxylic acid and/or hydroxyl groups. Insome embodiments, the method further comprises blocking one or more ofthe additional carboxylic acid groups. In other embodiments, the methodfurther comprises blocking one or more of the additional hydroxylgroups.

For a drug having one carboxylate group and at least one alcohol group(such as a primary or secondary alcohol), the polymer can be prepared byester bond formation methods known in the art. For example, the drug canbe acidified in aqueous solution using a strong acid such as, e.g.,para-toluenesulfonic acid or sulfuric acid, upon which it will undergoFischer esterification (Emil Fischer, Arthur Speier, Chemische Berichte1895, 28: 3252-3258). para-Toluenesulfonic acid (a solid) is preferredover sulfuric acid (a liquid), since it lacks the oxidizing propertiesof the latter and may conveniently be weighed. In some embodiments, theacidification is conducted in aqueous medium at a pH less than 2.0,e.g., pH approx 1.0 in aqueous para-Toluenesulfonic acid at aconcentration of 0.5 M. In general, for ester bond formation withnon-polymerizing reactants (e.g., ethanol and acetic acid to form ethylacetate), in the presence of strong acid, an equilibrium is reached andthe reaction does not go to completion. However, in the presentinvention, since the resulting drug homopolymer (or heteropolymer formedfrom 6-hydroxy-hexanoic acid and drug) is likely to be insoluble, itwill be removed from the aqueous reaction mixture by spontaneousprecipitation while forming, which will inhibit the reverse reaction,tending to drive the reaction towards completion. The precipitatedpolymer may be recovered by filtration and washing with water to removepara-Toluenesulfonic acid. Heating, up to about 80° C., may be requiredto drive the reaction, which may require from 1 to 8 hours to giveacceptable yield.

A variety of catalysts can be used to facilitate ester bond formation,which will be useful for the formation of the drug polymers of thepresent invention. Recent literature in this field is summarized athttp://www.organic-chemistry.org/namedreactions/fischer-esterification.shtmand applicable methods are summarized herein. In the following schemes,OH—R′ represents either the ring or chain hydroxyl of a prostacyclindrug molecule, with R′ representing the remainder of the molecule. Theother reactant represents the carboxylate end of a second prostacyclinmolecule. ‘R’ represents the moiety of a prostacyclin molecule exceptfor the carboxylate.

-   K. Ishihara, S, Nakagawa, A. Sakakura, J. Am. Chem. Soc., 2005, 127,    4168-4169.

-   T. Chen, Y. S. Munot, J. Org. Chem., 2005, 70, 8625-8627.

-   A. K. Chakraborti, et. al., J. Org. Chem., 2009, 74, 5967-5974.

In some embodiments, the polymer forming esterification reactions can beconducted at or near room temperature in order to avoid damage to themonomer and polymeric material. In some embodiments, the esterificationreactions are conducted at suitable temperature, e.g., at about 100° C.or below, at about 80° C. or below, at about 70° C. or below, at about60° C. or below, at about 50° C. or below, at about 40° C. or below, atabout 30° C. or below, or at about 25° C. or below. In some embodiments,the esterification reaction is conducted at room temperature. In someembodiments, the esterification reaction is conducted at about 25° C.

Conducting the esterification in the presence or absence of a blockingagent will result in a variety of drug release polymers. For example, inone embodiment, polymerization of treprostinil, e.g., via a Steglichesterification reaction, in the absence of blocking agents on thetreprostinil molecule, gives rise to a branched polymer (FIG. 2). Inthis form of the polymer, both the ring hydroxyl and the chain hydroxylbecome involved in backbone bonds of the polymer leading to a branchedstructure.

In one embodiment, a linear polymer can be formed is using a‘ring-hydroxyl-blocked’ form of prostacyclin. This is because the ringhydroxyl is the more reactive of the two hydroxyls, and its selectiveblockade is easier to achieve. First the carboxylate must be temporarilyprotected, in order to prevent reaction of the carboxylate with thehydroxyl-blocking reagent. FIG. 3 depicts a linear polymer formed byutilizing a ‘ring-hydroxyl-blocked’ form of treprostinil and involvingonly the chain hydroxyl and not the ring hydroxyl. The lesser reactivityof the available chain-hydroxyl groups (compared to the ring hydroxylgroups) will lead to slower reaction rates for this type of polymer.

In another embodiment, the chain-hydroxyl group can be blocked followingthe temporary protection of the carboxylate group, leading to theformation of another linear polymer depicted in FIG. 4. The rate andextent of polymerization of this form is anticipated to be greater thanfor the other homopolymers.

In embodiments where the polymers are made from blocked forms oftreprostinil, the blocking or protective group can either be removed orretained on the polymer. In some embodiments, removal of the blocking orprotective group after polymerization, under conditions that do nothydrolyze or otherwise break the ester bonds, will give rise todifferent forms of regular (i.e., linear or unbranched) drughomopolymer. In cases where the protective group is not toxic, it can beleft on, and the protected drug polymer used as a therapeutic agent. Theprotective group will likely undergo a slow spontaneous aqueoushydrolysis in vivo. In cases where the protective group is toxic, itmust first be removed before the polymer can be used as a therapeuticagent.

Various blocking agents and blocking strategies to achieve the necessaryselective blockade of ring or chain hydroxyl groups are known in theart. Further, blocking or protective groups which are amenable todeprotection under mild conditions, conducive to maintenance ofstability of the polymer and its drug moieties are desirable. In someembodiments, linear polymers may be formed by the use of protectinggroups to temporarily block the reactivity of particular target groupsin the prostacyclin or prostacyclin-drug molecule. In some embodiments,the linear polymers are prepared by creating prostacyclin structureswherein only one of the two hydroxyl (alcohol) groups is blocked (i.e.,the ring hydroxyl and the chain hydroxyl), leaving a molecule in whichthere are exposed a single reactive carboxylate and a single reactivehydroxyl.

In some embodiments it may also be necessary to temporarily block thecarboxylate group in order to allow an appropriate series of protectionand deprotection reactions to prepare a single-hydroxyl-blocked form.Suitable groups for the protection or blocking of hydroxyl andcarboxylate group are known in the art and are disclosed herein.Furthermore, particular ester groups that allow selective removal ofcarboxylate-protecting groups by enzymatic methods are known in the art,and include, but are not limited to heptyl esters (C₇H₁₅O₂CR),2-N-(morpholino)ethyl esters, choline esters (Me₃N⁺CH₂CH₂O₂Br⁻) (Sander,J. and H. Waldmann 2000, Chemistry-A European Journal 6(9), 1564-1577),(methoxyethoxy) ethyl esters and methoxyethyl esters (CH3OCH2CH2O2CR).These groups can be cleaved under very mild conditions, for example,enzymatic hydrolysis (Wuts, P. G. M., and Greene, T. W., 2007, Greene'sProtective Groups in Organic Synthesis. New Jersey, John Wiley & Sons,Inc; hereinafter Wuts 2007). These enzymatically-cleavable carboxylateblocking strategies may be particularly effective in creatingmono-hydroxy-protected forms of prostacyclin drugs for the formation oflinear polymers.

Several suitable blocking or protective groups for the hydroxyl groupsof the prostacyclin drugs which may be removed under mild conditionsconducive to maintenance of polymer stability are known in the art(e.g., Wuts 2007; Crouch, R. D., Tetrahedron 2013, 69(11): 2383-2417,hereinafter Crouch 2013). In some embodiments, the hydroxyl blocking orprotective group is a silyl ether group. Suitable silyl ether blockinggroups include, e.g., trimethylsilyl (TMS), t-butyldimethylsilyl(TBDMS), introduced as the chlorides TMSCl, TBDMSCl, which arespontaneously and selectively reactive towards hydroxyl groups. Thechloride forms react under mild conditions conducive to stability of thedrug molecule (e.g., TBDMSCl, imidazole, dimethylformamide, 25° C., 10h). As will be apparent to one skilled in the art, the differentialreactivity of different hydroxyl groups in a compound can be utilized toachieve selective blockade of one hydroxyl as opposed to other hydroxylgroups in the compound (Wuts 2007). In some embodiments, the blockinggroups can be utilized to selectively block the more-reactive ringhydroxyl compared. In other embodiments, the blocking groups can beutilized to selectively block the chain hydroxyl of a prostacyclincompound.

Suitable groups for the blocking or protecting the carboxylic acidgroups are known in the art and include, but are not limited to, allyl,methyl, ethyl, nitrobenzyl, dinitrobenzyl, tetrahydropyranyl,methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl, trimethylbenzyl,pentamethylbenzyl, methylenedioxybenzyl, benzhydryl, 4,4′dimethoxybenzhydryl, 2,2′4,4′-tetramethoxybenzhydryl, t-butyl, t-amyl,trityl, 4 methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl,2-phenyl-prop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl,2,2,2-trichloroethyl, b-(tri-methylsilyl)ethyl, b(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,4-nitrobenzylsulfonylethyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. In oneembodiment the carboxylic acid blocking or protective group is the2-N-(morpholino)ethyl ester, which is removable enzymatically.

Selective blockade can be achieved as follows, using treprostinil as anexample. By reacting carboxylate-protected treprostinil with TBDMS orTMS under gentle conditions (e.g., TBDMSCl, DMAP, Et₃N, DMF, 25° C., 12h), using stoichiometric amounts or modest molar excess of blockingagent, it will be possible to obtain selective derivatization of thering hydroxyl. Enzymatic removal of the carboxylate protection wouldthen yield a treprostinil derivative with free chain hydroxyl but with ablocked ring-hydroxyl and having a free carboxylate. Such a processwould be conducive to producing a linear polyester polymer (orco-polymer), wherein only the chain hydroxyl is involved in formation ofthe backbone ester bonds. Subsequent deprotection would yield a linearpolymer devoid of protecting groups.

In one embodiment, selective blockade of the chain hydroxyl group canalso be achieved by taking advantage of the differential base labilityof TBDMS and TMS ethers. For example, TBDMS ether groups are known to be10⁴ times more stable to basic hydrolysis than the TMS ether groups.Reaction of carboxylate-blocked treprostinil under the gentle conditionswith TMSCl, as discussed herein, will yield a treprostinil molecule witha TMS ether on the ring hydroxyl. Further reaction with TBDMS willproduce a double-blocked molecule wherein the chain hydroxyl is blockedwith TBDMS. Subsequent enzymatic deprotection of the carboxylatefollowed by deprotection of the double-hydroxyl-protected treprostinilunder mild base conditions will yield a treprostinil molecule whereinthe chain hydroxyl is blocked, but the ring hydroxyl is free.Polymerization of the latter form of mono-hydroxyl-protectedtreprostinil under suitable esterification conditions, e.g., by Steglichesterification, will give rise to a polymer wherein only the ringhydroxyl groups participate in ester bond formation, and form part ofthe backbone of the polymer. Subsequent removal of the remaining TBDMSgroup will give rise to a polymer wherein the only constituents aretreprostinil moieties. Various strategies for the selective protectionand deprotection of multiple hydroxyls using silyl ethers are known inthe art (e.g., Crouch, 2013), some which are suitable for the removal ofprotective groups such as TBDMS groups from the polymer.

Suitable mild conditions for deprotection of the linear homopolymersinclude those which avoid breakage of the inter-monomer ester bonds. Forexample, although acid and base hydrolysis are commonly used to removesilyl ether protecting groups, such conditions are also liable tohydrolyze the desirable inter-monomer ester bonds. Therefore, in someembodiments, mildly acid or mildly base hydrolysis conditions may beappropriate for the removal of the protecting groups from the polymer.In some embodiments, methods for the deprotection of silyl-etherprotected hydroxyls are those which do not use acid or base conditionsfor removal of the protecting group, and which are more conducive todeprotection of the polymers while preserving their backbone esterbonds. Examples of such methods include those which utilize catalyticfluoride under neutral conditions (DiLauro, et al., Journal of OrganicChemistry, 2011 76(18), 7352-7358.). This method will particularly besuitable for the deprotection of the polymers, i.e., removal of TMS orTDBMS, since it will likely preserve the inter-monomer ester bonds.Other examples include use of sulfated SnO₂(Bhure et al. SyntheticCommunications 2008, 38(3), 346-353) and Selectflour (Shah, S. T. A., S.Singh, et al. (2009), Journal of Organic Chemistry, 2009, 74(5),2179-2182) for the removal of silyl ether protecting groups frompolymers described herein, without risk of hydrolysis of inter-monomerester bonds.

In some embodiments of the drug homopolymers and blocked drughomopolymers of the present invention, if desired, the physical form andcharacteristics of the polymer can be adapted to resemble the propertiesof other known polymers by polymer formation in the presence of excessamounts, in molar terms, of co-monomers to form a heteropolymer. In someembodiments, in addition to the drug moiety, the polymer also includesone or more co-monomers. In some embodiments, the co-monomer iscovalently bonded to the carboxylic acid group of one drug moiety andthe hydroxyl group of a second drug moiety. In some embodiments, theco-monomers are selected so as to modify the properties of the drugrelease polymer in a desired manner. Examples of such co-monomersinclude, but are not limited to, 6-hydroxyhexanoic acid,hydroxyl-polyethyleneglycol-carboxylic acid, lactic acid, glycolic acidand beta-hydroxybutyrate.

In some embodiments, the polymer is designed to adapt to properties of aPolycaprolactone containing composition. For example, FIG. 5 shows aheteropolymer of treprostinil formed in the presence of6-hydroxyhexanoic acid as a co-monomer. 6-hydroxyhexanoic acid is theopen form of caprolactone (a cyclic ester) which is used to form thepolymer polycaprolactone using catalyzed ring-opening polymerizationmethod. In one embodiment, the 6-hydroxyhexanoic acid is incorporated asa co-monomer during the Steglich esterification of unblockedtreprostinil or blocked treprostinil. Incorporation of a molar excess(e.g., 10×) of the 6-hydroxyhexanoic acid gives rise to a polymer whosepredominating characteristic resembles that of polycaprolactone.Polycaprolactone can be melted at 60° C. allowing it to be molded intodiverse shapes for drug delivery (e.g., for a solid macro-implantdelivered subcutaneously or as a stent). In alternate embodiments, thecaprolactone-like heteropolymer (e.g., as depicted in FIG. 5) can beformed from emulsions as a nano- or micro-particulate suspension, ifrequired, without recourse to heat-melting, which imposes a finite riskof damaging the drug substance. Other biologically compatiblehydroxyl-containing carboxylic acid co-monomers, such as lactic acid andothers mentioned herein, would also be suitable for the purpose.

Polycaprolactone solid macro-implants have a longevity of up to threeyears in vivo and are the basis of several FDA approved products(Woodruff, M. A. and D. W. Hutmacher, Progress in Polymer Science, 2010,35(10), 1217-1256). Thus, it can be envisaged that thepolycaprolactone-like treprostinil heteropolymer (and thepoly-lactide-like treprostinil hetropolymer) could be used to achieve avery steady rate of release (achieving classic zero orderpharmacokinetics) determined by its surface area. Accordingly, in oneembodiment, the polycaprolactone-like treprostinil polymer can beadministered as a solid implant. In the case of thepolycaprolactone-like drug heteropolymer, much or all of the drug willlikely be released in prodrug form as soluble 6-hydroxyhexanoicacid-conjugate prodrug molecules, which would escape the implant sitebefore further hydrolysis to release free drug, thereby avoidingimplantation or injection site reactions (e.g., inflammation and pain)due to premature release of free prostacyclin. This featuredistinguishes the present technology from previously known compositionsin which prostacyclin drugs were embedded non-covalently inpolylactide-glycolide (PLGA) sustained release microparticles, as amonthly depot form (Obata et al., American journal of respiratory andcritical care medicine, 2008, 177(2), 195-20).

In some embodiments, the polymer is designed to adapt to properties of aPEG-containing composition, thereby resulting in a water soluble linearpolymer. For example, FIG. 6 shows the result of co-polymerization oftreprostinil in the presence of a hydroxyl-PEG-carboxylic acidco-monomer. In some embodiments, the PEG co-monomers have an averagemolecular weight of from about 500 to about 20000, about 800 to about10000 or about 1000 to about 5000 daltons. In some embodiments, the PEGco-monomers would be in the range of about 1 to about 5 kDa. Use of amolar excess (10x-50x) of the PEG moiety will result in a solublepolymer which would form a solution in saline for injection, and whichwould dissipate from the injection site before release of significantquantities of free drug that might cause injection site pain reactions.This is because, in the case of the present prostacyclin-PEGheteropolymer, ester bonds need to be cleaved at both ends of thetreprostinil moiety in order for drug release to occur. Therefore, therate of release will be an accelerating function of the molar abundanceof ‘ends’ which increases with time after successive hydrolysis events.

The PEG-heteropolymer can be administered using suitable methodsdiscussed herein. In some embodiments, the PEG-heteropolymer would bemost amenable to be administered as a subcutaneous injection, with theaim of avoiding injection-site reactions and achieving ‘acceleratingrelease’ in the bloodstream to counteract the exponential decay of thedrug-polymer conjugate in circulation. The drug release heteropolymersso formed can have an average molecular weight of from about 10,000 toabout 200,000 daltons. In some embodiments, the PEG heteropolymers havean average molecular weight of from about 15,000 to 150,000, about20,000 to 100,000, about 25,000 to 75,000, from about 30,000 to 50,000.

Other polymers, such as monomethoxy-PEG-OH or monomethoxy-PEG-COOH canbe used as chain termini individually or collectively, as well as chainterminating reagents. Such polymers, when used in chain termination, canbe added in excess after a timed interval of reaction progress. In thismanner it will be possible to achieve polymers with narrow dispersityi.e.

_(M) in the range 1.01-1.1. Incorporation of these PEG moieties dependson their relative concentration in the reaction mixture and can impartsolubility to the resulting polymer. When used as chain termini, the PEGmoieties have a suitable average molecular weight in the range of about5,000 to about 100,000 daltons, about 10,000 to about 60,000 daltons,about 20,000 to about 40,000 daltons, or about 25,000 to about 30,000daltons. For example, the use of a monomethoxy-PEG-OH in the Steglichesterification would result in a drug homopolymer with a PEG on thecarboxylate end of the polymer. Analogous use of a monomethoxy-PEG-COOHwould result in a drug homopolymer with a PEG on the other end. Thesepolymers are different from the polymers based onmono-hydroxy-PEG-carboxylate, wherein the drug monomers are interspersedamong the PEG monomers. Di-hydroxy PEG forms (i.e., having a hydroxylgroup at both ends of a linker PEG chain) can analogously be subjectedto Steglich esterification reactions along with prostacyclin drugmolecules having protected or unprotected groups. This would producesymmetrical polymer structures in which the PEG is located centrally,and flanked by homopolymers of the drug moiety either side, oriented inthe ‘carboxylate-in’ orientation as described below:—

The PEG-prostacyclin polymers prepared by these methods will haveunusually high drug loading capabilities compared to multi-arm PEGswhich have a maximum loading capacity of one drug molecule per arm(e.g., 4). No such limit applies to these polymer forms.

The polymers prepared using the methods described herein can be suitablycharacterized by methods known in the art. The detailed physicochemicalproperties of the drug release polymers disclosed herein, e.g.,solubility, rates of hydrolysis in vivo, can be experimentallydetermined. By characterizing the physical and chemical properties ofthe various polymers of the present technology, suitable qualities canbe selected for a given drug delivery method, e.g., for subcutaneousadministration, for incorporation into stents, etc. Further, for soliddosage forms, the rate of drug release can be controlled by manipulatingthe surface area of the drug-polymer solid. For example, in variousembodiments, the drug release polymers can be designed to be in ananoparticle, microparticle or macro form. For a given mass of drugrelease polymer, the rate of release of the drug will be maximal when itis made in nanoparticle form (e.g., 1 nm to 999 nm diameter). Inmicroparticle form (e.g., 10 μm diameter) it will be at least an orderof magnitude slower, and in macro-implant form (e.g., as a mesh, sheetor cylinder), it will be slower still. In macro form, the releasekinetic can be manipulated by choosing the shape of the implant (e.g., amesh or sheet instead of a cylinder) in order to achieve an optimalsurface area matched to the needs of drug release rate. The rate of drugrelease is generally proportional to the surface area of the implant andindependent of the mass of the implant. For the drug release polymersdisclosed herein, the rate of drug release in these macroimplementations is determined predominantly by the surface area, and notby the rate of aqueous or enzymatic hydrolysis of the ester bonds.Conversely, conventional drug polymer reversible conjugates, theintrinsic rate of bond hydrolysis, which determines release rate, can beadjusted only in a quantal manner by changing the chemical compositionof the polymer-drug conjugate, namely the drug-linker element. Thepresent drug release polymers are, therefore, more adjustable.

Unlike continuous infusion, the drug release polymer of the presenttechnology may be administered conveniently in a small volume by bolusinjection of a dose lasting one or more days. In alternativeembodiments, it may be made as an implant with duration of action up tothree years, with no risk of potentially dangerous bolus release ofdrug. This approach avoids concerns over the toxicity of polymers, suchas PEG in chronic high dosage use, but is also amenable to use with PEGand similar polymers where appropriate. It allows much higher loading interms of moles of drug per mole of polymer than can be achieved withexisting polymer systems. The drug polymer of the present technology is,in one aspect, a polyester, although it is designed to be biodegradableand resorbable by the body and can be manufactured under mild conditionsconducive to stability of the monomeric drug molecules and theirpolymerized moieties.

The physical properties of the polymer differ from that of the parentdrug molecule which is water soluble. This is because the major hydrogenbonding elements, i.e., the hydroxyl groups, are engaged in covalentester bonds and as such, the drug release polymer is likely to be lesswater soluble than the parent drug molecule. In some embodiments, ifrendered in nanoparticulate or microparticulate form, the drug releasepolymer will be suitable for subcutaneous injection. In otherembodiments, in nanoparticulate form, it will also be suitable forintravenous injection. Following injection, the drug undergoes a slowspontaneous hydrolysis by water molecules in the body which acceleratesas more bonds are broken. Because cleavage into monomeric forms is notrequired for solubility, soluble oligomers will escape the injectionsite at the site of injection sparing injection site pain andinflammatory reactions. Due to the higher reactivity of the ringhydroxyl, it is anticipated that most of the bonds in the polyesterhomopolymer will involve the ring hydroxyl as opposed to the chainhydroxyl group.

In another aspect, a pharmaceutical composition comprising any of thedrug release polymers described herein is provided. In some embodiments,the composition may include a pharmaceutically acceptable excipient.Pharmaceutically acceptable excipients are non-toxic, aidadministration, and do not adversely affect the therapeutic benefit ofthe compound of this invention. Such excipients may be any solid,liquid, semi-solid or, in the case of an aerosol composition, a gaseousexcipient that is generally available to one of skill in the art.Pharmaceutical compositions in accordance with the invention areprepared by conventional means using methods known in the art.

The drug release polymer is such that the monomeric prostacylinmolecular moieties form the entirety of the backbone of the polymer (inthe case of a drug homopolymer of the present invention) or an integralpart of the backbone of the polymer (in the case of a heteropolymer ofthe present invention). In both instances (homopolymer orheteropolymer), except for the two terminal drug moieties of the polymer(i.e. those moieties comprising respectively the carboxylate terminaland the hydroxyl terminal), the drug moieties of the polymer aretethered into the polymer by covalent ester bonds at both ends of thedrug molecule moiety, as distinct from being pendant moieties on the endof a polymer chain. By arranging the drug molecules in this way in thestructure of the polymer (i.e. tethered at both ends to the polymer andcomprising all or part of the polymer backbone, as distinct from‘pendant’ at the termini of a carrier polymer such as PEG), severalhydrolytic ester bond cleavage events are usually required before asingle drug molecule is released. This is because a single cleavageevent in a polymer chain gives rise (in the great majority of instances)to two smaller (daughter) polymer chains and not to any free drugmolecule, except in the statistically improbable event where thecleavage is at the terminal ester bond joining the first or last drugmonomer to the polymeric chain. The longer the chain, the moreimprobable it becomes that a hydrolytic cleavage event will take placeat the ester bond tethering the terminal drug moiety molecular unit,such that the rate of drug release from the polymer can be controlled bymanipulating the molecular weight of the polymer which determines itslength. This argument for delayed release of drug assumes, to somedegree, that the rate of hydrolysis will be the same for the ester bondsat the extreme ends of the polymer as for internal bonds. For solublepolymers, such as co-polymers of the present invention of a prostacyclinwith a PEG co-monomer, this arrangement is ensured by the extremelywell-hydrated and random-coil properties of PEG which will dominate theproperties of the heteropolymer. (In contrast, for insoluble polymers ofthe present invention, such as drug homopolymers or heteropolymers madewith 6-hydroxyhexanoic acid, being less solvated than PEG-prostacyclinheteropolymers, the ‘fully hydrated’ arrangement of the PEG-prostacyclinheteropolymer will not obtain and surface area of solvent exposure toextracellular fluids of the subcutaneous space, or other bodycompartment and fluid, will be the determining factor in rates ofhydrolysis and drug release). The hydrolytic behaviour of a solublepolymer of the present invention such as the PEG-prostacyclinheteropolymer and the probabilistic nature of its hydrolysis favoringrelease of pharmacologically inert fragments in the first instance canbest be conceived by reference to FIG. 7.

Shown in FIG. 7 is a drug homopolymer of the present invention having 11monomeric units (circles) and 10 inter-monomer bonds (A), at time zero(A) and at linear time intervals (B-H) after exposure to an aqueousenvironment, such as the extracellular fluid following a subcutaneousinjection, whereupon a stochastic process of aqueous hydrolysis willensue. Numbers to the right indicate number of free drug molecules;numbers to the left indicate number of ends. Initially (A) at time zero,there are only two monomeric moieties in the polymer that can give riseto free drug following a single hydrolytic aqueous hydrolysis event (a‘cut’). These are the end moieties (bold circles). The probability thata first cut will give rise to free drug is low therefore (1/5 in theinstance of a short polymer such as ‘A’. Following the first cut, whichmost likely (therefore) takes place at an internal bond, the abundanceof end groups capable of giving rise to free drug upon a new cut, hasdoubled (B), as has the probability that a new cut will give rise tofree drug. However, the probability that a new cut will occur at aninternal bond is still higher than the probability that a cut will takeplace at an end bond. Following the next cut, the products are ‘C’, butstill (in this particular stochastic instance) there is no free drugreleased. However, now the abundance of ends with the capability to giverise to free drug following a further cut has increased, such that thenext cut gives rise to D, wherein there are two molecules of free drugreleased. The initial hydrolytic events (i.e. the first two cuts)comprise a ‘lag’ phase wherein no free drug is released. Further cutsmay give rise either to free drug or to daughter fragments that arepharmacologically inactive. Eventually the abundance of ends decreasesresulting in a decline in the instantaneous rate of drug releaseapproaching a plateau in cumulative drug release over time. The‘accelerating’ property of drug release from polymers of this type ismore evident when one considers longer polymers. For example, for apolymer of n=101 monomers, the probability of an initial cleavage eventgiving rise to free drug is 1/50, such that the lag phase in release offree drug from such a polymer is longer, per unit mass of polymer, thanis the case for shorter polymers such as ‘A’ which have a greaterabundance of ends (expressed as ends per unit mass of polymer, or permole of monomer). For such larger polymer, probabilistically speaking,several cleavage events are required before any free drug is released.As the hydrolysis of the polymer proceeds, the rate of drug release willaccelerate. The behaviour of the drug homopolymer may be contrasted tothat of pendant polymer constructs (as described in the Ascendis patentscited earlier) wherein there is a fixed rate of drug release, and everycleavage event gives rise to liberation of a free drug molecule. Theprinciple of accelerating drug release (with an initial lag phase) willapply to soluble forms of the polymers of the present invention,particularly those made as heteropolymers with PEG moieties asco-monomers.

This ‘lag’ in the generation of free drug (though not absolute) has twoimportant effects. First, it allows the drug-polymer to escape theinjection site (in the case of a PEG-prostacyclin polymer) before freedrug is released. Secondly, as the concentration of polymer in thebloodstream declines, so its rate of drug liberation increases. Thesefactors act firstly to avoid local injection site reaction, due to theaction of free drug at the injection site, and secondly to counteractthe exponential decline in drug concentration that would normally followa the administration of a conventional drug-covalent-release polymer. Bypreventing, substantially, the initiation of drug release at theinjection site, the pain, inflammation or other adverse reactions at theadministration site can be prevented or reduced. The inert polymerfragments must first reach the bloodstream before they can begin torelease drug to a significant extent, adequate to elicit the desiredeffects of the drug.

The drug release polymers and their pharmaceutical compositions can beformulated for different routes of administration. These include, butare not limited to, oral, transdermal, intravenous, intraarterial,pulmonary, rectal, nasal, vaginal, lingual, inhalation, injection orinfusion, including intradermal, subcutaneous, intramuscular,intravenous, intraosseous, and intraperitoneal. Other sustained releasedosage forms may include, for example, in depot, an implant, a stent ora transdermal patch form. In some embodiments, the pharmaceuticalcomposition is administered as an injection, e.g., subcutaneous orintramuscular injection. In other embodiments, the pharmaceuticalcomposition is administered as an implant. Various dosage forms may beprepared using methods that are standard in the art (see e.g.,Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, EastonPa. 1980).

In another embodiment, a reconstituted or liquid pharmaceuticalcomposition comprising the drug release polymer is administered via afirst method of administration and a second reconstituted or liquidpharmaceutical composition comprising drug release polymer isadministered via a second method of administration, eithersimultaneously or consecutively. Said first and second method ofadministration can be any combination of topical, enteraladministration, parenteral administration, inhalation, injection, orinfusion, intraarticular, intradermal, subcutaneous, intramuscular,intravenous, intraosseous, and intraperitoneal, intrathecal,intracapsular, intraorbital, intracardiac, transtracheal, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, intraventricularor intrasternal administration.

In some embodiments, the polymer is administered as an injection. Unlikethe free drug molecule, the drug release polymers of the presenttechnology can be injected without causing injection site pain, sincethey diffuse from the injection site, in prodrug-oligomeric form,entering the blood and lymphatic systems, before release of free drug byfurther aqueous hydrolysis. In some embodiments, the polymer isadministered via inhalation. In other embodiments, the polymer isadministered orally. Upon inhaled or oral administration, the oligomericforms would undergo a gradual sustained release of free drug avoidingthe dose-limiting ‘spike’ or ‘peak’ in blood concentration thatgenerally ensues following oral or inhaled delivery of free drug.

Unlike continuous infusion in conventional controlled releaseformulations, the drug release polymer of the present technology may beadministered conveniently in a small volume by bolus injection of a doselasting one or more days. In alternative embodiments, it may be made asan implant with duration of action up to three years, with no risk ofpotentially dangerous bolus release of drug. This approach avoidsconcerns over the toxicity of polymers, such as PEG in chronic highdosage use, but is also amenable to use with PEG and similar polymerswhere appropriate. It allows much higher loading in terms of moles ofdrug per mole of polymer than can be achieved with existing polymersystems. The drug polymer of the present technology is, in one aspect, apolyester, although it is designed to be biodegradable and resorbable bythe body and can be manufactured under mild conditions conducive tostability of the monomeric drug molecules and their polymerizedmoieties.

In some embodiments, the drug release polymers of the present technologycan be administered as a subcutaneous injection or to inhaled delivery.In other embodiments, where needed, the polymer, in a nanoparticle orsoluble form, can be administered intravenously. In yet anotherembodiment, being a polyester, the polymer can be administered could beused in the formation or coating of plastic stents for slow sustainedrelease of drug at suitable anatomical sites (e.g., within the arterialvessels of the pulmonary circulation) effecting localized drug deliveryto the target tissue (e.g., in the case of pulmonary hypertension) whilesparing systemic side effects. Such stents are known in the art, forexample bioresorbable coronary stents for the sustained release ofanti-proliferative drugs such as paclitaxel and everoliumus, to preventrestenosis after balloon angioplasty, and have recently been reviewed byOrmiston, J. A. and P. W. Serruys, Circulation. Cardiovascularinterventions, 2009, 2(3), 255-260. The first example of the use of abioabsorbable (bioresorbable) stent in humans used polylactic acid (apolyester), which was pioneered by Tamai and colleagues (Onuma, Y., S.Garg, et al., EuroIntervention journal of EuroPCR in collaboration withthe Working Group on Interventional Cardiology of the European Societyof Cardiology 5 Suppl F: F109-111, 2009). Analogously, according to therationale of the present technology, techniques for the formation ofpolylactide (polylactic acid, PLA) and polylactide-glycolide (PLGA)could be used for the covalent incorporation of a pro-inflammatory drugssuch as prostacyclins, e.g., treprostinil, iloprost, cicaprost andberaprost. Covalent incorporation, as part of a homopolymer orheteropolymer, allows desorption of the drug from the site as atransient covalent prodrug form, which may then be hydrolyzed to theactive form during circulation.

Depot arrangements, such as stents, can also be utilized to administerdrugs which have very short pharmacokinetics for conventional modes ofdrug administration and delivery (e.g., intravenous) due to theirinherent chemical instability. Such drugs include, e.g., naturalprostacyclin molecule, i.e., prostaglandin-I2. These drugs, whenutilized as the drug release polymer of the present technology, can bereleased locally into the pulmonary arterial circulation and will have alesser availability in the general circulation outside of the pulmonarysystem, thereby avoiding systemic side effects and allowing higher dosesto be administered locally to the affected vascular (arterial) tissuesof the lung to achieve a more favorable therapeutic ratio.

Administration by subcutaneous injection is most suitable for solubleforms of the drug release polymer, such as the linear PEG-prostacyclinco-polymer. In some embodiments, a vial of polymer solution can belyophilized from water or dried from solvent by evaporation undervacuum. The dry drug release polymer can then be reconstituted justbefore use as a solution or suspension in a medium suitable forsubcutaneous injection. Such mediums include, e.g., phosphate-bufferedphysiological saline of pH, or buffers such as succinate, or citratecould be used to administer saline solutions buffered at pH's moreconducive to polymer stability, e.g., pH 6.0. For subcutaneousinjection, suitable polymer lengths can include chain lengths from aboutn=2 up to about n=100, about n=10 up to about n=100, about n=15 up toabout n=80, about n=20 up to about n=70 or about n=25 up to about n=50.

For inhaled administration, the polymer is, in one embodiment, at leasta homodimer (for administration in liquid aerosol form). For inhaledadministration, suitable polymer lengths can include chain lengths fromabout n=25 up to about n=200, about n=50 up to about n=150 about n=60 upto about n=100, or about n=70 up to about n=90. In some embodiments, thepolymer length is n=50 or greater. In some embodiments, the polymer hassufficient length and particle size so that it can be administered as asolid form in a metered dose dry powder inhaler. For example, the drugrelease polymer can have particles having mean or median size of about 3micrometers, favoring deposition in the alveoli of the lung for optimalaccess to pulmonary arterioles. Low oligomer forms (such as a dimer or atrimer) would be less amenable to uptake than the monomer drug moleculesuch that lung administration of polymer forms would form a local depotwhich would gradually elute free drug from the alveoli into thepulmonary arterioles. In contrast to non-polymerized, free drug, whichis soluble and rapidly escapes the lung tissue into the generalcirculation where it causes systemic side-effects, the polymeric formsof drug (dimer, trimer and polymers) would be ‘captive’ in the alveoli,forming a local, inert, sustained release reservoir. Further, becausethe present polymers need to undergo hydrolysis before absorption canoccur, they avoid the spike in blood concentration that occursimmediately following inhalation of non-polymerized drugs, therebyavoiding the dose limiting side effects associated with inhaled drugformulations. Moreover, the polymeric formulations provide a moreconstant level of free drug in the vicinity of the pulmonary arteriolesthan the inhaled forms of free drugs.

Polymers and compositions described herein maybe used alone or incombination with other compounds. When administered with another agent,the co-administration can be in any manner in which the pharmacologicaleffects of both are manifest in the patient at the same time. Thus,co-administration does not require that a single pharmaceuticalcomposition, the same dosage form, or even the same route ofadministration be used for administration of both the compound of thisinvention and the other agent or that the two agents be administered atprecisely the same time. However, co-administration will be accomplishedmost conveniently by the same dosage form and the same route ofadministration, at substantially the same time. Obviously, suchadministration most advantageously proceeds by delivering both activeingredients simultaneously in a novel pharmaceutical composition inaccordance with the present invention.

The present technology is different in a number of respects fromconventional drug release solutions known in the art. Firstly, manysustained release strategies are known to use covalent ester bonds. Inthe present technology, the bond is not to a polymer carrier (as inclassical drug-polymer covalent release conjugates) or to a substituentgroup (as in classical prodrug strategies for non-polymer drugs), butrather to another molecule of the drug itself. As such, it eliminatesconcerns about the toxicology of the polymer or substituent element,since the polymer dissolves, upon aqueous hydrolysis, to release onlythe drug, such that the chemical toxicology of the new polymer isvirtually identical to that of the parent drug molecule, which generallyis known. Further, the cleavage of the drug release polymers of thepresent technology does not inevitably result in release of free drug.This is because, initially, random cleavage of the new polymer resultspredominantly in the release of polymer fragments which are, as yet,inactive. Therefore, premature cleavage of the polymer, e.g., uponstorage, before administration, does not give rise to significantamounts of free drug that might lead to contamination and adversereactions, e.g., causing injection site reaction in case of aninjectable formulation.

Compared to classical polymer prodrug strategies, the present drugrelease polymers exhibit flexibility in control of drug releaseproperties. Unlike a conventional covalent polymer release strategy,wherein the rate of release of the drug is dictated by the fixed rate ofhydrolysis of the bond attaching the drug to the polymer (e.g., an esterbonded PEG-drug prodrug conjugate), for the drug release polymer of thepresent technology, the rate of release of free drug is a complexfunction of the rate of ester bond hydrolysis and the length of thepolymer. The drug release polymers which have shorter lengths and have agreater abundance of ends per unit mass will give rise to more rapidliberation of free drug. On the other hand, drug release polymers withlonger lengths will result in slower release of free drug, such thatdrug release rates can be controlled by controlling the length oraverage length of the drug during polymer synthesis. As such, the rateof release of the drug for such a polymer is more of an analog functionless restricted by the quantal variation between different chemistriesof attachment and can be ‘tuned’ to maximum effect. In embodiments wherethe polymer is administered in the insoluble ‘implant’ or ‘stent’ forms,as exemplified by the heteropolymer with 6-hydroxyhexanoic acid, therate of drug release can be controlled by manipulating the surface areaof the implant or the stent.

In some embodiments, only cleavage of the end bonds gives rise to activeproduct. As successive cleavages occur randomly along the length of thepolymer, the concentration of ends increases exponentially, and so toodoes the probability that a new random cleavage will occur at an end,i.e., the rate of drug release is proportional to the abundance of‘ends.’ Depending upon the length, the polymer would be insoluble orsoluble in aqueous solutions. In some embodiments, where the drugrelease polymer is insoluble, it can be administered as a local depot(subcutaneous or by dry powder inhalation), or incorporated into stents.Shorter polymer chain lengths, e.g., dimmers and trimers, would likelyresult in soluble forms. The rate of active drug release is more likelyto be ‘analog’ in character and could be tuned by adjustment of polymerlength. This is advantageous for avoiding adverse reactions, forexample, to avoid the spike in blood concentration following inhalation,possibly avoiding dose limiting systemic side effects.

In yet another aspect, a method of diagnosing, treating, controlling,delaying or preventing in a mammalian patient, e.g., in a human, in needof the treatment of one or more conditions, diseases or disorderscomprising administering to said patient a therapeutically effectiveamount of a drug release polymer of the present technology or apharmaceutical composition comprising the drug release polymer or apharmaceutically acceptable salt thereof, is provided. It will beunderstood that the conditions, diseases or disorders will depend on thedrug moiety which is being polymerized and its therapeutic activity. Forexample, if the drug moiety has anti-cancer activity, it will beadministered to a cancer patient; if the drug moiety has ananti-inflammatory activity, it will be administered to a patient whosuffers from an inflammatory disease, like rheumatoid arthritis,inflammatory bowel disease or Crohn's disease; a drug moiety which hasneurological activity will be administered to a patient suffering from aneurological disease like Alzheimer's disease or Parkinson's disease,and so on and so forth.

Exemplary conditions, diseases or disorders that can be prevented and/ortreated with the drug release polymer of the present technology include,but are not limited to, pulmonary hypertension, ischemic diseases (e.g.,peripheral vascular disease including peripheral arterial disease,Raynaud's phenomenon including Raynaud's disease and Raynaud's syndrome,scleroderma including systemic sclerosis, myocardial ischemia, ischemicstroke, renal insufficiency), ischemic ulcers including digital ulcers,heart failure (including congestive heart failure), portopulmonaryhypertension, interstitial lung disease, idiopathic pulmonary fibrosis,conditions requiring anticoagulation (e.g., post MI, post cardiacsurgery), thrombotic microangiopathy, extracorporeal circulation,central retinal vein occlusion, atherosclerosis, inflammatory diseases(e.g., COPD, psoriasis), hypertension (e.g., preeclampsia), reproductionand parturition, cancer or other conditions of unregulated cell growth,cell/tissue preservation. In one embodiment, the present technologyrelates to a treprostinil controlled release polymer or apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof for use in a method of treating or preventing a disease ordisorder which can be treated and/or prevented by treprostinil. In oneembodiment, the disease or disorder is pulmonary arterial hypertension.Non-small-cell lung cancer is another indication to which the presentinvention is applicable, wherein treprostinil (or other prostacyclindrug such as iloprost) can be used as an agonist of the Wnt signallingpathway, arresting the growth of lung cancer cells and inhibiting newtumour formation (Tennis, M. A., et al., Neoplasia, 2010, 12(3):244-253.).

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES Example 1 Preparation of Polymer Compound (A)

The polymer forming reaction is achieved most favorably by amodification of the well known Steglich esterification (Hofle, G., W.Steglich, et al. 1978) as here described for the drug homopolymer ofFIG. 2. Dissolve 30.5 mg 0.78 mmol of treprostinil in dichloromethane(DCM 25 mL) and deionized H₂O (600 μ

). Add dimethylaminopyridine (DMAP 760 mg, 6.24 mmol) and EDC HCl (1.19g, 6.24 mmol) dissolved in DCM (10 ml). Stir the reaction mixture atroom temperature until reaction is complete, or reaches a plateau (asjudged by HPLC/MS measuring free treprostinil), i.e. for 4-8 h or for 16h overnight, at which time no further free treprostinil is beingconsumed in polymer formation. Add the DCM solution to excess water,while stirring vigorously, and evaporate off the dichloromethane in arotary evaporator. Recover the particulate polymer by filtration, andwash with water to remove excess EDC and by-products, and any unreactedtreprostinil. Further purification can be effected by dissolving thedried polymer in DCM and conducting gel permeation chromatography in DCMaccording to methods known in the art. The first (broad) peak to elutein such chromatography will be treprostinil polymers, later elutingpeaks are residual contaminants and may be discarded.

An alternative method to achieve the drug homopolymer of FIG. 2 is toapply the esterification method of Sharghi, Babak et al. 1998, as heredescribed. To a mixture of MeSO₃H (1.0 mL, 15 mmol) and Al₂O₃ (0.27 g,3.0 mmol), 2.0 mmol of treprostinil is added. The mixture is stirred andheated in an oil bath at 80° C. for 7-120 min. Then the mixture ispoured into water, at which time the polymer precipitates, and isrecovered by filtration along with the Al₂O₃, and washing with water (toremove free treprostinil). The recovered polymer and Al₂O₃ mixture isthen resuspended in water and the suspension is extracted twice withethyl acetate or chloroform (20 mL) to dissolve the polymer leavingbehind the alumina. The organic layer is then washed with a saturatedsolution of sodium bicarbonate (20 mL). Finally, the organic layer isdried over calcium chloride (CaCl₂) and evaporated in vacuum to obtain aresidue, which is the polymer product.

It is to be understood that while the invention has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of theinvention. Other aspects, advantages and modifications within the scopeof the invention will be apparent to those skilled in the art to whichthe invention pertains

All patents, patent applications, publications and references citedherein are incorporated by reference in their entirety to the extent asif they were individually incorporated by reference.

What is claimed is:
 1. A pharmaceutical composition comprising aplurality of releasable drug moieties, wherein each drug moietycomprises at least one carboxylic acid group and at least one hydroxylgroup, wherein at least some drug moieties are covalently attached toeach other through said at least one hydroxyl group of one drug moietyand said at least one carboxylic acid group of another drug moiety,thereby forming a polymer.
 2. The pharmaceutical composition of claim 1,wherein the covalent attachment is an ester bond formed between said atleast one hydroxyl group and said at least one carboxylic group.
 3. Thepharmaceutical composition of claim 1, wherein the drug moiety is aprostacyclin compound.
 4. The pharmaceutical composition of claim 3,wherein the prostacyclin compound is selected from the group consistingof epoprostenol, treprostinil, beraprost, iloprost, cicaprost, andprostaglandin
 12. 5. The pharmaceutical composition of claim 4, whereinthe prostacyclin compound is treprostinil.
 6. The pharmaceuticalcomposition of claim 3, wherein the prostacyclin compound is a compoundof Formula (I)

wherein

represents a single or a double bond; Z¹ and Z² each independentlyrepresents an O or CH₂; p=0 or 1; m=1, 2, or 3; R¹ represents a H or anacid protective group; R² and R³ each independently represents a H or ahydroxyl protective group; R⁴ represents H and the other represents aC₁₋₆ alkyl; and R⁵ represents a C₁₋₆ alkyl group or C₂₋₈ alkynylenegroup.
 7. The pharmaceutical composition of claim 1, further comprisinga co-monomer covalently bonded to the carboxylic acid group of one drugmoiety and the hydroxyl group of a second drug moiety.
 8. Thepharmaceutical composition of claim 7, wherein the polymer is insolublein water.
 9. The pharmaceutical composition of claim 7, wherein thepolymer is soluble in water.
 10. The pharmaceutical composition of claim7, wherein the co-monomer is selected from the group consisting of6-hydroxyhexanoic acid, beta-hydroxybutyric acid, hydroxyl-polyethyleneglycol-carboxylic acid, lactic acid, and glycolic acid.
 11. Thepharmaceutical composition of claim 1, wherein the drug moieties thatform the polymer have a structure selected from the group consisting offollowing Formulae (IIa), (IIb) and (IIc):


12. The pharmaceutical composition of claim 1 further comprising apharmaceutically acceptable excipient.
 13. The pharmaceuticalcomposition of claim 12, wherein the composition is in a form suitablefor injection.
 14. The pharmaceutical composition of claim 13, whereinthe form is suitable for a subcutaneous or intramuscular injection. 15.The pharmaceutical composition of claim 12, wherein the composition isin a form suitable for implant.
 16. A method for producing a drugrelease polymer, comprising esterifying a drug moiety which comprises atleast one carboxylic acid group and at least one hydroxyl group in thepresence of a coupling agent and a catalyst.
 17. The method of claim 16,wherein the coupling agent isN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide orN,N′-Dicyclohexylcarbodiimide.
 18. The method of claim 16, wherein thecatalyst is 4-(Dimethylamino)pyridine.
 19. The method of claim 16,further comprising blocking one or more carboxylic acid groups of thedrug moiety in excess of one carboxylic group, prior to esterification.20. The method of claim 16, further comprising blocking one or morehydroxyl groups of the drug moiety in excess of one hydroxyl group,prior to esterification.
 21. The method of claim 20, wherein the one ormore hydroxyl groups are blocked using trimethylsilyl chloride ort-butyldimethylsilyl chloride.
 22. A method of treating, controlling,delaying or preventing in a mammalian patient in need of the treatmentof one or more conditions comprising administering to said patient adiagnostically and/or therapeutically effective amount of thepharmaceutical composition of claim 1.